Abstract
The yeast galactose switch operated by the Gal4p-Gal80p-Gal3p regulatory module is a textbook model of transcription regulation in eukaryotes. The Gal80 protein inhibits Gal4p-mediated transcription activation by binding to the transcription activation domain. In Saccharomyces cerevisiae, inhibition is relieved by formation of an alternative Gal80-Gal3 complex. In yeasts lacking a Gal3p ortholog, such as Kluyveromyces lactis, the Gal1 protein (KlGal1p) combines regulatory and enzymatic activity. The data presented here reveal a yet unknown role of the KlGal80 N terminus in the mechanism of Gal4p activation. The N terminus contains an NLS, which is responsible for nuclear accumulation of KlGal80p and KlGal1p and for KlGal80p-mediated galactokinase inhibition. Herein, we present a model where the N terminus of KlGal80p reaches the catalytic center of KlGal1p causing enzyme inhibition in the nucleus and stabilization of the KlGal1-KlGal80p complex. We corroborate this model by genetic analyses and structural modelling and provide a rationale for the divergent evolution of the mechanism activating Gal4p.
Highlights
Transcription regulation in response to the environment occurs in all organisms and is essential for cellular homeostasis
Nuclear localization of Gal80p in K. lactis depends on the N terminus
The whole genome duplication in the Saccharomyces lineage was accompanied by rearrangements, deletions and duplications of chromosome segments (Lynch & Conery, 2000; Kellis et al, 2004), and second, the loss of the LAC genes disabled lactose metabolism, which occurred in S. cerevisiae and independently in many other ascomycetes
Summary
Transcription regulation in response to the environment occurs in all organisms and is essential for cellular homeostasis. Pioneering work on the regulation of transcription by galactose in yeast gave rise to the Douglas–Hawthorne model of the GAL regulon (Douglas & Hawthorne, 1972; Oshima, 1991). This model assumes that a gene-specific transcription activator (Gal4p) is inhibited by Gal80p. When a yeast cell has access to galactose the Gal80p-mediated inhibition is relieved by the Gal3p protein, which functions as a galactose transducer These three regulatory proteins, namely Gal4p, Gal80p, and Gal1/ 3p, represent the heart of the “galactose switch.”. Insights into the formation of the Gal1–Gal complex are central to the understanding of the GAL switch and the activation of Gal4p. The ScGal1p variant has only residual regulatory activity because its affinity to ScGal80p is lower than that of Gal3p (Lavy et al, 2016)
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